In recent years, it has been shown that, with regard to peptide synthesis, a block synthesis method or a chemical native ligation method is effective for the synthesis of a long chain peptide. In both the aforementioned methods, a peptide thioester is essential.
Examples of known thioester synthesis methods using an Fmoc solid-phase peptide synthesis method include: a method of deprotecting an Fmoc group using a weak base instead of piperidine (Direct Preparation of Peptide Thioesters Using an Fmoc Solid-Phase Method, X. Li, T. Kawakami, S. Aimoto, Tetrahedron Lett., 1998, 39, 8660-8672); a method using a Safety Catch linker of Kenner (it has been known that this method involves difficulty in introduction of the linker into a resin or introduction or cutout of the first amino acid residue, and thus this method has been applied to only a limited range.) (Solid-Phase Synthesis of Peptide C-Terminal Thioesters by Fmoc/tBu Chemistry, R. Ingenito, E. Bianchi, D. Fattori, A. Pessi, J. Am. Chem. Soc., 1999, 121, 11369-11374); a method which comprises extending a peptide chain by the Fmoc method, cutting it out, and then converting carboxylic acid to a thioester using Me2AlCl-thiol (there are cases where a functional group of amino acid side chain is impaired.) (Fmoc-Compatible Solid-Phase Peptide Synthesis of Long C-Terminal Peptide Thioesters, A. Sewing, D. Hilvert, Angew. Chem. Int. Ed., 2001, 40, 3395-3398); and a method of protecting thiol (this method is disadvantageous in that it can be applied only to Gly, and in that a side chain protecting group cannot be selectively deprotected.) (Fmoc Solid-Phase Synthesis of Peptide Thioesters by Masking as Trithioorthoesters, J. Brask, F. Albericio, K. J. Jensen, Org. Lett., 2003, 5, 2951-2953). In addition, a publication (Native Chemical Ligation through in Situ 0 to S Acyl Shift, P. Botti, M. Villan, S. Manganinello, H. Gaertner, Org. Lett., 2004, 6, 4861-4864) describes a method, which comprises introducing a residue having an ester bond that has a protected thiol group on the side chain, conducting a peptide elongation reaction in the solid phase, eliminating a protecting group from the thiol group after cutting it out, so as to cause an O- to S acyl shift in a molecule, thereby synthesizing a thioester. However, the stability of an ester portion under basic conditions during deprotection of Fmoc in such an Fmoc solid-phase peptide synthesis is unknown. Moreover, another publication (Fmoc-Solid-Phase Synthesis of Peptide Thioesters Using an Intramolecular N, S-Acyl Shift, N. Ollivier, J-B. Behr, O. El-Mahdi, A. Blanpain, O. Melnyk, Org. Lett., 2005, 7, 2647-2650) describes a method which comprises performing alkylation on nitrogen via a Mitsunobu reaction by using alcohol having a protected thiol group, and then deprotecting the protecting group of the thiol group, so as to synthesize a thioester by an acyl shift to thiol in a molecule. However, this method is problematic in terms of the yield of the Mitsunobu reaction.